Glypican-3 Modulates BMP- and FGF-Mediated Effects during Renal Branching Morphogenesis

摘要

ThekidneyoftheemGpc3/emminus;/mouse,anovelmodelofhumanrenaldysplasia,ischaracterizedbyselectivedegenerationofmedullarycollectingductsprecededbyenhancedcellproliferationandovergrowthduringbranchingmorphogenesis.Here,weidentifycellularandmolecularmechanismsunderlyingthisrenaldysplasia.Glypican-3(GPC3)deficiencywasassociatedwithabnormalandcontrastingratesofproliferationandapoptosisincortical(CCD)andmedullarycollectingduct(MCD)cells.InCCD,cellproliferationwasincreasedthreefold.InMCD,apoptosiswasincreased16-fold.ExpressionofemGpc3/emmRNAinuretericbudandcollectingductcellssuggestedthatGPC3canexertdirecteffectsinthesecells.Indeed,GPC3deficiencyabrogatedtheinhibitoryactivityofBMP2onbranchformationinembryonickidneyexplants,convertedBMP7-dependentinhibitiontostimulation,andenhancedthestimulatoryeffectsofKGF.SimilarcomparativedifferenceswerefoundincollectingductcelllinesderivedfromGPC3-deficientandwildtypemiceandinducedtoformtubularprogenitorseminvitro,/emsuggestingthatGPC3directlycontrolscollectingductcellresponses.WeproposethatGPC3modulatestheactionsofstimulatoryandinhibitorygrowthfactorsduringbranchingmorphogenesis./p/div